Resuscitation from sudden cardiac arrest (SCA) is typically initiated in patients with ongoing ischemia and ventricular fibrillation that, even if successful, is commonly followed by repeated rearrest. Despite significant efforts to improve resuscitation from SCA, survival remains poor prompting NIH to identify resuscitation as a high priority for emergency care research. In preliminary studies, we observed in patients and in an in vivo translational model of resuscitation from SCA, that rearrest is common and paralleled by increased cardiac alternans, a beat-to-beat alternation in the ECG T wave and cellular repolarization that is associated with arrhythmias. Cardiac alternans is especially heightened during acute ischemia/reperfusion, which is rampant during resuscitation. We contend that rearrest during resuscitation is due to the development of spatially discordant alternans, which is alternans of opposite phase in neighboring myocardial regions that dramatically magnifies repolarization gradients. However, there are still many unanswered questions regarding the causal relationship between discordant alternans and arrhythmogenesis and, surprisingly, it has never been proven to occur in a clinically realistic situation. Not only do we believe that discordant alternans is an important cause of rearrest during resuscitation, but also that it can be targeted using clinically translatable treatments. For instance, our preliminary data and many other studies suggest that normalizing Ca2+ dysregulation or gap junction coupling during resuscitation can suppress discordant alternans and, thus rearrest. Finally, because discordant alternans dynamically forms spatial gradients of repolarization, we contend it can be detected non-invasively by the progression of ECG T wave oscillation patterns, including alternans (doubling) or higher order oscillations (e.g. tripling, complex). If true, it may be possible to predict the acute occurrence of rearrest using an ECG biomarker. Our hypotheses will be tested with the following aims. 1) Determine the mechanistic relationship between discordant alternans, repolarization gradients, and rearrest in our fully instrumented in vivo model of resuscitation. 2) Determine if pharmacologically mitigating discordant alternans in the same model can prevent rearrest during resuscitation, thereby improving outcomes. 3) Develop and test an ECG biomarker for predicting rearrest in resuscitation patients. To achieve these aims, we will utilize sophisticated instrumentation and signal processing techniques in a realistic clinical scenario. We have also established a highly translational collaboration that combines expertise in emergency medicine, cardiac arrhythmia, and clinical electrophysiology. Our scientific environment provides a unique opportunity to develop a better understanding of arrhythmia mechanisms relevant to resuscitation in order to develop novel and effective therapies.